Experimental colitis modulates the functional properties of NMDA receptors in dorsal root ganglia neurons

University of Florence, Florens, Tuscany, Italy
AJP Gastrointestinal and Liver Physiology (Impact Factor: 3.8). 09/2006; 291(2):G219-28. DOI: 10.1152/ajpgi.00097.2006
Source: PubMed


N-methyl-D-aspartate (NMDA) receptors (NMDARs) on spinal afferent neurons regulate the peripheral and central release of neuropeptides involved in the development of hyperalgesia. We examined the effect of experimental colitis on the molecular and functional properties of NMDARs on these neurons. Lumbosacral dorsal root ganglia (DRG) were collected from adult rats 5 days after the induction of colitis for whole cell patch-clamp recording, Western blot analysis, and quantitative RT-PCR. Compared with neurons from control rats, those taken from animals with colitis had a threefold higher density of NMDA currents in both retrograde-labeled, colon-specific, and unlabeled DRG neurons. Increased current densities were not observed in DRG neurons taken from thoracic spinal levels. There was no significant change in NMDA or glycine affinity or in voltage-dependent Mg2+ inhibition; however, there was a 10-fold decrease in sensitivity to the NR2B subunit-selective antagonist ifenprodil. Quantitative RT-PCR and Western blot analysis indicated a 28% increase in the expression of NR2B with little or no change in the other three NR2 subunits. The addition of the Src family tyrosine kinase inhibitor PP2 (10 microM) decreased NMDAR currents in neurons from colitis but not control rats. Conversely, pretreatment of DRG neurons from control animals with 100 microM sodium orthovanadate increased NMDAR currents and decreased ifenprodil sensitivity to levels similar to those observed in neurons from animals with colitis. In conclusion, colonic inflammation upregulates the activity of NMDARs in all DRG neurons within ganglia innervating this tissue through mechanisms involving increased expression and persistent tyrosine phosphorylation.

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    • "This potentiation of NMDA receptors in primary afferents probably occurs in chronic pain disorders other than neuropathic pain. Thus, in a rat model of colitis there was an increase in NMDA receptor currents in DRG neurons mediated by SFKs (Li et al., 2006). Perhaps this can explain why Liu et al. (1997) found that intrathecal NMDA induced NK1R internalization: an undetected inflammation in their rats could have potentiated these NMDA receptors. "
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    ABSTRACT: NMDA receptors in primary afferent terminals can contribute to hyperalgesia by increasing neurotransmitter release. In rats and mice, we found that the ability of intrathecal NMDA to induce neurokinin 1 receptor (NK1R) internalization (a measure of substance P release) required a previous injection of BDNF. Selective knock-down of NMDA receptors in primary afferents decreased NMDA-induced NK1R internalization, confirming the presynaptic location of these receptors. The effect of BDNF was mediated by tropomyosin-related kinase B (trkB) receptors and not p75 neurotrophin receptors (p75(NTR) ), because it was not produced by proBDNF and was inhibited by the trkB antagonist ANA-12 but not by the p75(NTR) inhibitor TAT-Pep5. These effects are probably mediated through the truncated form of the trkB receptor as there is little expression of full-length trkB in dorsal root ganglion (DRG) neurons. Src family kinase inhibitors blocked the effect of BDNF, suggesting that trkB receptors promote the activation of these NMDA receptors by Src family kinase phosphorylation. Western blots of cultured DRG neurons revealed that BDNF increased Tyr(1472) phosphorylation of the NR2B subunit of the NMDA receptor, known to have a potentiating effect. Patch-clamp recordings showed that BDNF, but not proBDNF, increased NMDA receptor currents in cultured DRG neurons. NMDA-induced NK1R internalization was also enabled in a neuropathic pain model or by activating dorsal horn microglia with lipopolysaccharide. These effects were decreased by a BDNF scavenger, a trkB receptor antagonist and a Src family kinase inhibitor, indicating that BDNF released by microglia potentiates NMDA receptors in primary afferents during neuropathic pain.
    European Journal of Neuroscience 03/2014; 39(9). DOI:10.1111/ejn.12516 · 3.18 Impact Factor
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    • "Despite extensive studies on the role of postsynaptic NMDARs in the development and maintenance of pathological pain including neuropathic pain, the role of presynaptic NMDARs of primary afferents in the spinal nociceptive sensory processing remains elusive. NMDARs are present in primary afferent terminals in the spinal dorsal horn and dorsal root ganglion neurons, as repeatedly confirmed both anatomically and physiologically (Liu et al. 1994; Bardoni et al. 2004; Li et al. 2006; Zeng et al. 2006). Activation of presynaptic NMDARs with intrathecal injection of the NMDAR agonist NMDA results in increased release of substance P from primary afferents in adult rats (Liu et al. 1997). "
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    ABSTRACT: Activation of N-Methyl-D-aspartate (NMDA) receptors is a crucial mechanism underlying the development and maintenance of pain. Traditionally, the role of NMDA receptors in the pathogenesis of pain is ascribed to their activation and signaling cascades in postsynaptic neurons. In this study, we determined if presynaptic NMDA receptors in the primary afferent central terminals play a role in synaptic plasticity of the spinal first sensory synapse in a rat model of neuropathic pain induced by spinal nerve ligation. Excitatory postsynaptic currents (EPSCs) were recorded from superficial dorsal horn neurons of spinal slices taken from young adult rats. We showed that increased glutamate release from the primary afferents contributed to the enhanced amplitudes of EPSCs evoked by input from the primary afferents in neuropathic rats. Endogenous activation of presynaptic NMDA receptors increased glutamate release from the primary afferents in neuropathic rats. Presynaptic NMDA receptors in neuropathic rats were mainly composed of NR2B receptors. The action of presynaptic NMDA receptors in neuropathic rats was enhanced by exogenous D-serine and/or NMDA and dependent on activation of protein kinase C. In contrast, glutamate release from the primary afferents in sham-operated rats was not regulated by presynaptic NMDA receptors. We demonstrated that the lack of NMDA receptor-mediated regulation of glutamate release in sham-operated rats was not attributable to low extracellular levels of the NMDA receptor agonist and/or coagonist (D-serine), but rather was due to the insufficient function and/or number of presynaptic NMDA receptors. This was supported by an increase of NR2B receptor protein expression in both the dorsal root ganglion and spinal dorsal horn ipsilateral to the injury site in neuropathic rats. Hence, suppression of the presynaptic NMDA receptor activity in the primary sensory afferents is an effective approach to attenuate the enhanced glutamatergic response in the spinal first sensory synapse induced by peripheral nerve injury, and presynaptic NMDA receptors might be a novel target for the development of analgesics.
    The Journal of Physiology 01/2013; 591(7). DOI:10.1113/jphysiol.2012.250522 · 5.04 Impact Factor
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    • "Peripheral NMDARs are targets for the treatment of neuropathic pain (Wu & Zhuo, 2009). NMDARs expressed on spinal afferent neurons are upregulated in the lumbosacral dorsal root ganglia (DRG) following experimental colitis (Li et al., 2006). Peripheral NMDARs play a role in behavioral pain responses to colonic distention, suggesting that these receptors are important in visceral pain transmission (McRoberts et al., 2001). "
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    ABSTRACT: A recent study--comparing those with depression, somatization, comorbid depression+somatization, and controls--showed specific changes in the tryptophan catabolite (TRYCAT) pathway in somatization, specifically lowered tryptophan and kynurenic acid, and increased kynurenine/kynurenic acid (KY/KA) and kynurenine/tryptophan ratios. These findings suggest that somatization and depression with somatization are characterized by increased activity of indoleamine 2,3-dioxygenase and disorders in kynurenine aminotransferase activity, which carry a neurotoxic potential. This chapter reviews the evidence that the TRYCAT pathway may play a pathophysiological role in the onset of somatization and depression with somatization and, furthermore, suggests treatment options based on identified pathophysiological processes. Lowered plasma tryptophan may be associated with enhanced pain, autonomic nervous system responses, gut motility, peripheral nerve function, ventilation, and cardiac dysfunctions. The imbalance in the KY/KA ratio may increase pain, intestinal hypermotility, and peripheral neuropathy through effects of KY and KA acid, both centrally and peripherally, at the N-methyl-d-aspartate receptor (NMDAR), G-protein-coupled receptor-35 (GPR35), and aryl hydrocarbon receptor (AHr). These alterations in the TRYCAT pathway in somatization and depression may interface with the role of the mu-opioid, serotonin, and oxytocin systems in the regulation of stress reactions and early attachment. It is hypothesized that irregular parenting and insecure attachment paralleled by chronic stress play a key role in the expression of variations in the TRYCAT pathway-both centrally and peripherally-driving the etiology of somatization through interactions with the mu-opioid receptors. Therefore, the TRYCAT pathway, NMDARs, GPR35, and AHrs may be new drug targets in somatization and depression with somatizing. We lastly review new pathophysiologically driven drug candidates for somatization, including St. John's wort, resveratrol, melatonin, agomelatine, Garcinia mangostana (γ-mangostin), N-acetyl cysteine, and pamoic acid.
    07/2012; 88:27-48. DOI:10.1016/B978-0-12-398314-5.00002-7
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